Trypanosoma brucei is a flagellated protozoan parasite that is the causative agent of African sleeping sickness in humans and nagana in cattle. Sleeping sickness is a reemerging disease in sub-Saharan Africa where ~60 million people live at risk of infection. Sleeping sickness is fatal if untreated and no vaccines are available. Current drugs are antiquated, toxic and difficult to administer, a situation that is exacerbated by the development of drug resistance. Thus, there is a critical and urgent need to understand novel features of parasite biology and identify new drug targets. T. brucei is transmitted to the bloodstream of a mammalian host through the bite of an infected tsetse fly vector. In both hosts, T. brucei is in intimate contact with tissue surfaces and exhibits an implicit requirement for sensing and signaling to guide parasite migration and differentiation. This is especially apparent in the tsetse. Currently, little is known about how surface contact modulates trypanosome biology. Recently, we reported that T. brucei engages in social behavior when cultivated on semi-solid agarose plates. This behavior, termed social motility, is characterized by the formation of multicellular communities that sense external stimuli and communicate with one another to coordinate movement of the population. The discovery of social behavior in T. brucei reveals a level of complexity and cooperativity in protozoan behavior that was previously unrecognized. In other microbial pathogens social behaviors offer numerous advantages and studies of social interactions in bacteria have revolutionized our understanding of microbial pathogenesis. We hypothesize that social behavior in T. brucei provides similar advantages for trypanosome development and pathogenesis and that systems used by T. brucei for cell-cell signaling in social motility overlap with systems used to sense and respond to host signals. The current proposal will identify genes and mechanisms underlying social behavior in trypanosomes. Given the widespread social interactions among other microbes we expect our studies to have broad relevance among parasitic protozoa. PUBLIC HEALTH RELEVANCE: African trypanosomes and related parasites are the source of morbidity and mortality in several million people worldwide and diseases caused by these pathogens are among the world's most neglected diseases. The proposed project will identify genes and mechanisms required for social behavior in trypanosomes. In bacterial pathogens, social interactions have profound influences on disease pathogenesis, but this paradigm has only recently been applied to parasites and we therefore expect to uncover novel concepts and mechanisms that apply broadly to other parasitic infections.